The combination of PET and MRI into a hybrid device offers great potential as a research tool in both the clinical and preclinical setting. In contrastto PET/CT, simultaneous PET/MRI is unique as it allows for concurrent acquisition of images from both modalities which is especially valuable in monitoring time-varying processes, for example the effect of an intervention during imaging, or when the highest degree of spatial registration between PET and MRI is required. We have recently conducted in vivo imaging studies in models of acute cerebral hypoxia-ischemia, in which rapid changes in physiology occur on the order of minutes, providing an interesting example of an application for simultaneous PET/MRI. While PET/MR systems have recently become available for human studies, the preclinical field is still lacking truly integrated state-of-the-art systems that would enable these kinds of studies to be done in small animals in support of basic and preclinical research. Furthermore, existing small animal PET/MRI prototypes for simultaneous imaging do not exploit the full potential of detection sensitivity, as they do not use depth-of-interaction (DOI)-encoding detectors and therefore compromise on detector thickness and efficiency to maintain spatial resolution low count rate scenarios. They also are often limited in their absolute quantification accuracy owing to limited stability or the absence of reliable attenuation correction techniques. The purpose of this proposal is to develop a state-of-the-art whole body combined DOI-PET/MRI for mice and rats which will use thick scintillation crystals to provide a sensitivity of ~12-16% and a spatial resolution on the order of 1.0 mm. This will be the highest sensitivity preclinical PET/MRI system developed to date and is designed for quantitative dynamic PET studies in combination with advanced MRI sequences for research in the areas of neurology, oncology and cardiology. This system will employ MR-compatible silicon photomultiplier (SiPM)-based pixelated LSO block detectors with continuous DOI encoding based on dual- ended readout with a novel and highly efficient readout approach. We will furthermore develop a procedure to accurately estimate subject attenuation and attenuation of MR coils and subject bed inside the PET/MRI FOV to provide full correction of attenuation and scatter thus enhancing quantification accuracy in small-animal systems. Finally we will investigate the quantitative performance of this PET/MRI system based on phantom experiments that carefully measure any mutual interference between the PET and MRI systems and also by performing a proof-of-concept small-animal study in a cerebral ischemia-hypoxia model to demonstrate quantitative accuracy of in vivo PET and MRI measurements acquired simultaneously versus separately.